1. Field of the Invention
This invention relates generally to the use of calpain inhibitors, in particular to methods for the treatment of peripheral axonal degeneration. Other aspects of the invention relate to the use of peptide α-ketoamide compounds to treat pathological conditions including neural pathologies, and combinations of anti-hyperproliferative agents with peptide α-ketoamides for the treatment of hyperproliferative conditions.
2. Related Art
Peripheral neuropathy is a major dose-limiting complication of commonly used anti-cancer agents, including vincristine, cisplatin, and paclitaxel (Taxol®). Paclitaxel, a microtubule toxin derived from the western yew tree, is particularly effective against solid tumors, but causes a predominantly sensory neuropathy that may be severe enough to necessitate cessation of treatment. The neuropathy is characterized by degeneration of sensory axons, manifesting clinically as numbness, pain, and loss of balance [Lipton, R. B., S. C. Apfel, J. P. Dutcher, R. Rosenberg, J. Kaplan, A. Berger, A. I. Einzig, P. Wiernik and H. H. Schaumburg (1989). “Taxol produces a predominantly sensory neuropathy.” Neurology 39 (3): 368-73]. Paclitaxel causes a similar sensory neuropathy in rodents that provides a useful experimental model for the treatment of peripheral neuropathies.
Calpains are ubiquitous cytosolic proteolytic enzymes involved in both physiological and pathological cellular functions. They are calcium-dependent enzymes belonging to the family of cysteine proteases. Limited activation of calpains results in modification or activation of protein receptors, enzymes, and cytoskeletal proteins. Pathological cellular insults lead to more generalized calpain activation, resulting in cytoskeletal degradation and cell death.
Calpain activation likely occurs due to sustained elevation of intracellular calcium that is a common feature of models of neuronal injury [Bartus, R. (1997). “The calpain hypothesis of neurodegeneration: evidence for a common cytotoxic pathway.” Neuroscientist 3: 314-327]. Thus, there is a need for compositions and methods of treating pathologies related to calpain activation.
Because neuronal pathologies, in particular neuropathy, can have a dramatic impact on quality of life of patients, there is also a need for compositions and methods for treating these disorders, in particular, compositions and methods for treating pathologies with little or reduced side effects such as neuropathy.
There is still another need for methods and compositions for treating axonal degeneration.